Dihydropyrimidine dehydrogenase deficiency (DPD) in GI malignancies: Experience of 4 years.
Dihydropyrimidine dehydrogenase deficiency (DPD) in GI malignancies: Experience of 4 years.
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DOI：
10.1200/jco.2006.24.18_suppl.2056
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发表时间：
2006-06
期刊：
影响因子：
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通讯作者：
R. Mehra;L. Mattison;L. Ledbetter;H. Ezzeldin;R. Diasio;M. Saif
中科院分区：
文献类型：
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作者：
R. Mehra;L. Mattison;L. Ledbetter;H. Ezzeldin;R. Diasio;M. Saif
2056背景：5-氟尿嘧啶（5-FU）是胃肠道恶性肿瘤治疗的重要组成部分。虽然正常的DPD酶活性在5-FU催化剂中是速率限制性的，但其缺乏可增加生物可利用的5-FU合成代谢产物的浓度，导致5-FU相关毒性综合征。DPD缺乏时，应停用5-FU。关于卡培他滨（CAP）在该人群中的安全性数据很少。方法2001年至2005年，在UAB对5-FU和CAP过度毒性后的患者进行DPD缺乏症检测。DPD活性测定采用PBMC放免法、DPYD基因DHPLC分型法、2- 13 C尿嘧啶呼气试验（UraBT）。结果：在23例胃肠道恶性肿瘤（小肠、胃、胰腺、HCC和结直肠）患者中，7例（30%）DPD缺乏。在这7例患者中，DPD活性范围为0.064 - 0.18 nmol/min/mg。年龄范围为51-75岁，男：女比= 1.3：1，种族包括高加索人（71%）、非洲裔美国人（14%）和南亚人（14%）。4例接受5-FU/LV（2例Roswell; 2例马约）; 2例CAP（1800 mg/m2）; 2例高剂量推注5-FU（1400 mg/m2）+PN 401（三乙酰尿苷）治疗。毒性包括粘膜炎（71%）、腹泻（43%）、恶心（29%）、记忆丧失/精神状态改变（43%）、血细胞减少（43%）、低血压（14%）、呼吸窘迫（14%）、急性肾衰竭（14%）和重度皮疹（43%）。1例患者在马约方案后再次使用CAP，仅在手背表面引起3级HFS。PN 401组1例患者发生3级面部皮疹，为最严重毒性。对第二例有严重白细胞减少症的PN 401患者的DPYD基因进行了基因型分析，发现其为杂合突变（IVS 14 +1 G>A，DPYP*2A）。2例患者的UraBT显示1例患者为DPD缺陷（DOB 50为112.8; PDR为49.4%），另1例患者为临界正常值（DOB 50为130.9; PDR为52.5%）。有2例毒性相关死亡（28%）：CAP组1例，5-FU + PN 401组1例。结论DPD缺乏症在多个民族中存在。有CAP毒性的患者也应该进行DPD缺乏症的检测。PN 401在DPD缺乏症中挽救5-FU毒性的作用尚不清楚。在给予5-FU或CAP之前，使用UraBT筛查患者的DPD缺乏症，可能会降低毒性风险。未来的研究应该验证这种技术。[表：见正文]。
2056 Background: 5-Fluorouracil (5-FU) is an integral part of treatment of GI malignancies. While normal DPD enzyme activity is rate limiting in 5-FU catabolism, its deficiency could increase concentrations of bioavailable 5-FU anabolic products leading to 5-FU related toxicity syndrome. With DPD deficiency, 5-FU is discontinued. Data regarding safety of capecitabine (CAP) in this population is scarce. METHODS Patients were tested for DPD deficiency after excessive toxicities from 5-FU and CAP at UAB between 2001 and 2005. DPD activity was evaluated by PBMC radio assay, genotyping of DPYD gene by DHPLC, or 2-13C uracil breath test (UraBT). RESULTS Of 23 patients with GI malignancies (small intestine, gastric, pancreatic, HCC, and colorectal) evaluated, 7 (30%) were DPD deficient. Among these 7 patients, DPD activity ranged from 0.064 - 0.18 nmol/min/mg. Age ranged from 51-75 years, M:F ratio = 1.3:1, and ethnicities included Caucasian (71%), African-American (14%) and South-Asian (14%). Four were treated with 5-FU/LV (2 Roswell; 2 Mayo); 2 CAP (1800mg/m2); and 2 high dose bolus 5-FU (1400mg/m2) + PN401 (tri-acetyluridine). Toxicities included mucositis (71%), diarrhea (43%), nausea (29%), memory loss/altered mental status (43%), cytopenias (43%), hypotension (14%), respiratory distress (14%), acute renal failure (14%), and severe skin rashes (43%). Re-challenge with CAP in 1 patient after the Mayo regimen caused grade 3 HFS only on dorsal surfaces of hands. One patient on PN401 had a grade 3 facial rash as the worst toxicity. Genotypic analysis of the DPYD gene in the second on PN401, who had severe leucopenia, demonstrated a heterozygous mutation (IVS14+1 G>A, DPYP*2A). UraBT in 2 patients revealed 1 to be DPD-deficient (DOB50 of 112.8; PDR of 49.4%) and borderline normal values (DOB50 of 130.9; PDR of 52.5%) in a second patient. There were 2 toxicity-related deaths (28%): 1 on CAP and 1 on 5-FU + PN401. CONCLUSIONS DPD deficiency was observed in several ethnicities. Patients with CAP toxicities should also be tested for DPD deficiency. Role of PN401 in rescuing 5-FU toxicity in DPD deficiency is not clear. Screening patients for DPD deficiency prior to administration of 5-FU or CAP, using UraBT, could potentially lower risk of toxicity. Future studies should validate this technique. [Table: see text].